Proposed research has a long-term goal to unravel the molecular mechanisms by which mutations of Sod1 gene encoding Cu, Zn superoxide dismutase (SOD1) produce selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. The central hypothesis of this proposal is that bicarbonate anion enhances the peroxidative potential of SOD1 and its mutant variants via generation of a highly potent carbonate anion radical (CO3.-). Specific Aims include demonstration of CO3.- radical generation using purified enzymes; studies on the role of carbonate radical in hydroxylation, oxidation and nitration reactions; characterization of bicarbonate effects on oxidation/nitration reaction catalyzed by spinal cord extracts of transgenic ALS mutant mice and wild type animals. Four major analytical techniques to be used include electron spin resonance spectroscopy (ESR) and spin trapping; HPLC; UV-visible spectroscopy and chemiluminescence.